Human immunodeficiency virus (HIV) infection is a growing epidemic within today's world population. Highly active antiretroviral therapies (HAART) are becoming increasingly effective at decreasing or even eliminating the serum viral load of HIV positive individuals, resulting in increased life spans. Unfortunately, long-term harmful side effects (hyperlipidemias, lipodystrophy and insulin resistance) of HAART therapeutics are becoming evident. The mechanism(s) by which HIV protease inhibitors (PI) therapy leads to dysregulation of sterol and lipid metabolism is unclear. The liver is the major organ responsible for maintaining lipid homeostasis in the body. The proposed experiments in this new application will explore the mechanism(s) by which different HIV PIs alter hepatic cholesterol, bile acid and fatty acid metabolism. The specific aims of this application are: 1) Determine the effects of the most commonly used HIV PI (ritonavir, indinavir, nelfinavir, Iopinavir, atazanavir) on cholesterol, bile acids and fatty acid metabolism using primary adult rat hepatocytes as a model system; 2) Determine the effects of HIV PI on hepatic cholesterol, fatty acid, and bile acid metabolism and lipoprotein profiles in a mouse in vivo model 3) Elucidate the mechanism(s) where by indinavir (and other HIV PIs) alters hepatic cholesterol and bile acid metabolism in primary rat hepatocytes. Test the hypothesis that HIV PIs alters the intracellular movement of cholesterol and/or protein turnover rates of sterol responsive element binding proteins (SREBPs). Knowledge of how HIV PI alter lipid metabolism may allow for more effective, long term approaches for treating HIV infected individuals. [unreadable] [unreadable]